Erythroid differentiation sensitizes K562 leukemia cells to TRAIL-induced apoptosis by downregulation of c-FLIP

Ville Hietakangas, Minna Poukkula, Kaisa M Heiskanen, Jarkko T Karvinen, Lea Sistonen, John E Eriksson

Research output: Contribution to journalArticleScientificpeer-review


Regulation of the apoptotic threshold is of great importance in the homeostasis of both differentiating and fully developed organ systems. Triggering differentiation has been employed as a strategy to inhibit cell proliferation and accelerate apoptosis in malignant cells, in which the apoptotic threshold is often characteristically elevated. To better understand the mechanisms underlying differentiation-mediated regulation of apoptosis, we have studied death receptor responses during erythroid differentiation of K562 erythroleukemia cells, which normally are highly resistant to tumor necrosis factor (TNF) alpha-, FasL-, and TRAIL-induced apoptosis. However, upon hemin-mediated erythroid differentiation, K562 cells specifically lost their resistance to TNF-related apoptosis-inducing ligand (TRAIL), which efficiently killed the differentiating cells independently of mitochondrial apoptotic signaling. Concomitantly with the increased sensitivity, the expression of both c-FLIP splicing variants, c-FLIP(L) and c-FLIP(S), was downregulated, resulting in an altered caspase 8 recruitment and cleavage in the death-inducing signaling complex (DISC). Stable overexpression of both c-FLIP(L) and c-FLIP(S) rescued the cells from TRAIL-mediated apoptosis with isoform-specific effects on DISC-recruited caspase 8. Our results show that c-FLIP(L) and c-FLIP(S) potently control TRAIL responses, both by distinct regulatory features, and further imply that the differentiation state of malignant cells determines their sensitivity to death receptor signals.

Original languageEnglish
Pages (from-to)1278-91
Number of pages14
JournalMolecular and Cellular Biology
Issue number4
Publication statusPublished - Feb 2003
MoE publication typeA1 Journal article-refereed


  • Alternative Splicing
  • Apoptosis/physiology
  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins/genetics
  • Caspase 8
  • Caspase 9
  • Caspases/metabolism
  • Cell Differentiation/drug effects
  • Cytochrome c Group/metabolism
  • Death Domain Receptor Signaling Adaptor Proteins
  • Down-Regulation
  • HL-60 Cells/metabolism
  • Hemin/pharmacology
  • Humans
  • Intracellular Membranes
  • Intracellular Signaling Peptides and Proteins
  • K562 Cells/metabolism
  • Membrane Glycoproteins/metabolism
  • Membrane Potentials/drug effects
  • Mitochondria/metabolism
  • Protein Isoforms
  • Proto-Oncogene Proteins c-bcl-2/drug effects
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor/metabolism
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha/metabolism
  • bcl-X Protein


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